This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Intimal hyperplasia forms as a result of blood vessel damage and disease. In damaged vessels, platelets bind to and become activated on exposed collagen within the blood vessel. The activated platelets support thrombus formation, release inflammatory cytokines and recruit monocytes from the blood into the vessel tissue. The monocytes then secrete factors including cytokines that stimulate smooth muscle cell (SMC) migration into the intimal layer, and extracellular matrix (ECM) secretion, culminating in intimal hyperplasia. Dysfunctional endothelium, which is present in all diabetic patients due to uremia and other metabolic disorders, support platelet binding and activation similar to exposed collagen. In addition, dysfunctional and damaged endothelium supports leukocyte migration from blood into the blood vessel wall. Dysfunctional endothelium also loosens cell-cell junctions, causing them to become leaky due to gaps between the cell membranes, and potentially exposes underlying collagen in these gaps, which is then accessible to platelet binding. Thus, exposed collagen present due to loss of endothelial cells (ECs), as a result of mechanical vessel damage during handling, and dysfunctional and damaged ECs, supports intimal hyperplasia.
Loss of glycocalyx, the anionic glycosaminoglycan layer covering the endothelium is a hallmark of dysfunctional endothelium and inflammation. Loss of the glycocalyx unmasks cell surface receptors including ICAM and VCAM, which are expressed in chronic inflammation and endothelial cell (EC) dysfunction. Glycocalyx loss also exposes receptors P-selectin and E-selectin, which are transiently expressed on the cell surface due to damage and inflammation, and chronically expressed in dysfunctional endothelium as is the case in diabetic patients. The selectins facilitate leukocyte rolling on the ECs, which is the first step to monocyte and neutrophil migration into the vessel wall. Following rolling, the leukocytes bind more firmly to ICAM and VCAM. They then migrate into the tissue where they release cytokines, and stimulate SMC migration to the intima and ECM synthesis. The end result is intimal hyperplasia, which prevents outward remodeling and can promote long-term thrombosis.